The present invention relates to a thermosensitive cyclotriphosphazene-platinum complex conjugate which can be administered systemically or locally and has an excellent anticancer activity, its preparation method and an anticancer agent containing the same as an active ingredient. More particularly, the compound of the present invention is a biodegradable cyclotriphosphazene-platinum complex conjugate exhibiting thermosensitivity in the temperature range including the body temperature.
The present inventors have found that the derivatives obtained by nucleophilic substitution of chlorine atoms in hexachlorocyclotriphosphazene ((NPCl.sub.2).sub.3) with a low or high molecular weight hydrophilic poly(alkoxyethylene glycol) and a hydrophobic amino acid ester exhibit thermosensitivity (Korean patent application No. 99-48800). The present inventors have succeeded in the preparation of their platinum complexes by introducing the (diamine)platinum(II) ion to the hydrolyzed amino acid groups of these trimeric derivatives. To our surprise, these novel trimeric platinum complex conjugates also exhibited thermosensitivity in a wide temperature range including the body temperature as well as high anticancer activity. These new thermosensitive platinum complex conjugate anticancer agents showing a controlled release property has never been reported. These compounds can be administered systemically or locally since the targeted drug delivery is possible using their thermosensitivity. We expect, therefore, these new compounds will provide a new and significantly improved therapeutic regimen in the treatment of solid tumors.
Thermosensitive polymers in the present invention refer to the polymers that can be solubilized in water at low temperatures but precipitates above a certain critical temperature due to the rapid decrease of their water-solubility. When such a phase transition is reversible, the phase transition temperature is called a lower critical solution temperature(LCST) or a cloud point. Below LCST, the hydrogen bonding between the polymer-water molecules is stronger than the hydrophobic interaction between the polymer-polymer molecules. As the temperature increases, however, the hydrogen bonding between the polymer-water molecules weakens whereas the hydrophobic interaction between the polymer-polymer molecules increases resulting in the precipitation of polymers in aqueous solution.
These thermosensitive polymers were widely studied in many fields is including mainly drug delivery systems, medical biomaterials, thin films, the separation process of biochemical reactions, cosmetics and optics. However, most of the conventional thermosensitive organic polymers are known to be hydrolytically non-degradable. In recent years, a few biodegradable polymers were reported (Jeong, B. et. al., Nature, 388, 860 (1997); Song, S.-C. et. al., Macromolecules, 32, 2188(1999); Lee, S. B. et. al., Macromolecules, 32, 7820 (1999)). Up to date, however, no thermosensitive anticancer drug has been reported. Cisplatin, a platinum complex, approved as an anticancer agent in 1979 by FDA in the United States has been used as one of the most effective chemotherapeutic agents to treat a variety of cancers such as testicular, ovarian, bladder, and head and neck cancers. Its use is limited, however, due to its high toxicity (LD.sub.50 =13 mg/Kg, M. J. Cleare, Biochimie 60, 835(1978)). Even though the second-generation anticancer agent, carboplatin exhibits much lower toxicity than cisplatin (LD.sub.50 =180 mg/Kg, M. J. Cleare, Biochimie 60, 835(1978)), it is not widely used since it is lower in anticancer activity and more expensive than cisplatin. Therefore, there is a great need for a third-generation anticancer agent that has higher and wider anticancer activity with lower toxicity than cisplatin.